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Default Conformational entropy of FK506 binding to FKBP12 determined by NMR relaxation and molecular dynamics simulations.

Conformational entropy of FK506 binding to FKBP12 determined by NMR relaxation and molecular dynamics simulations.

Conformational entropy of FK506 binding to FKBP12 determined by NMR relaxation and molecular dynamics simulations.

Biochemistry. 2018 Feb 07;:

Authors: Solomentsev G, Diehl C, Akke M

Abstract
FKBP12 (FK506 binding protein 12 kDa) is an important drug target that attracts a great deal of interest as a model system for computational drug design and studies on the role of protein dynamics in ligand binding. NMR spectroscopy is uniquely suited to experimentally probe protein dynamics on a wide range of timescales. Order parameters, describing amplitudes of motion on the pico- to nanosecond timescale, take a central role because they are often used to validate molecular dynamics simulations and can provide estimates of the conformational entropy. Here we update and extend currently available order parameters of the apo and FK506-bound forms of FKBP12. Using 15N and 2H NMR relaxation experiments, we characterized backbone and side chain methyl-axis order parameters to gain information on entropic contributions to ligand binding arising from changes in the conformational fluctuations of FKBP12. Binding of FK506 to FKBP12 results in localized changes in backbone order parameters, most notably for residues E54 and I56, which coordinate the ligand. Significant changes in the methyl-axis order parameter are observed for residues in the binding site, specifically I56, I90, and I91, as well as for more remote sites, including V63 and V98. On average, the order parameters increase slightly upon FK506 binding, indicating that the sampled degrees of free-dom give an unfavorable entropic contribution to the free energy of binding of T?S = -18 ± 2 kJ/mol at 293 K. We complemented the exper-imental studies with molecular dynamics simulations, which provide an estimate of the total change in conformational entropy of FKBP12 upon binding FK506, yielding T?S = -26 ± 9 kJ/mol. Both these values are significant compared to the total entropy of binding determined by isothermal titration calorimetry and referenced to 1 mM reactant concentration, T?S = -29 ± 1 kJ/mol, which also includes contributions from desolvation as well as translational and rotational entropy. We compared our present results to previously reported order parameters for the rapamycin-FKBP12 complex, revealing subtle differences in the response to ligand binding, despite the high structural homology be-tween the two complexes and their near-identical ligand-FKBP12 interactions. These results highlight the delicate dependence of protein dynamics on drug interactions, which goes beyond the view provided by static structures. These results reinforce the notion that changes in protein conformational entropy can make an important contribution to the free energy of ligand binding.


PMID: 29412644 [PubMed - as supplied by publisher]



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